1. Field of the Invention.
The subject of this invention is a novel group of inositol-phosphat derivatives and their use as calcium-antagonistic compounds for different pharmacological uses such as for the treatment of cardio-vascular diseases.
2. Description of the Prior Art
It is now generally accepted that hydrolysis of phosphatidylinositol(4.5)bisphosphate (PIP2) by receptor- and G-protein mediated activation of PIP2-specific phospholipase C (PIP2-PLC) results in the formation of two different second messengers in the cytoplasm of cells: d-myo inositol(1.4.5)trisphosphate (IP3) and diacylglycerol. IP3 can bind to an appropriate receptor on intracellular organelles causing release of Calcium. Two metabolic pathways terminate this receptor-mediated Calcium release: a) the action of an IP3-3-kinase, phosphorylating the 3-position leading to Inositol (1.3.4.5) tetrakisphosphate (IP4) and b) the action of an IP3-5-phosphatase leading to Inositol(1.4)bisphosphate. Since the cell is expending energy in form of ATP to generate IP4, IP4 is considered to be a putative second messenger, possibly regulating further steps in the Calcium-Metabolism of cells (M. J. Berridge, (1987) Ann. Rev. Biochem. 56, 159-193; and M. J. Berridge and R. F. Irvine, (1989) Nature 341, 197-205). The importance of IP3 as a Calcium mobilizing intracellular second messenger has lead to the synthesis of IP3 and derivatives thereof.
Preparation of Phosphorothioates acting as long-lived agonists have been described (A. M. Cooke et al., (1987) J. Chem. Soc. Chem. Commun. 1525-1526; and J. Strupish et al., (1988) Biochem. J. 253, 901-905). However, there have been no reports in IP3-analogues acting as IP3-receptor- and therefore intracellular Calcium-antagonists. In addition, analogues of IP4 acting as long lived agonists or antagonists, are not available yet.
It is an object of this invention, to describe the synthesis of specific IP3-, IP4- and PIP/PIP2-Analogues modified at the 5-Position. A further surprising aspect of this invention is to describe antagonists of the IP3-receptor, acting as intracellular Calcium-antagonists. These substances Can generally be used as highly active pharmacological compounds, especially they can be used as antithrombotic agents and in a variety of other cardiovascular diseases.